The coagulation cascade is a normal physiological process which aims at preventing significant blood loss or hemorrhage following vascular injury. There are times, however, when a blood clot (thrombus) will form when it is not needed. For instance, some high risk conditions such as acute medical illness, prolonged immobilization, surgery, or cancer can increase the risk of developing a blood clot which can potentially lead to significant consequences such as atherosclerotic cardiovascular disease and/or abnormal cardiac rhythms.
The coagulation cascade consists of a series of steps in which a protease cleaves and subsequently activates the next protease in the sequence. Each protease can activate several molecules of the next protease in the series, amplifying this biological cascade. The final result of these reactions is to convert fibrinogen, a soluble protein, to insoluble threads of fibrin. Together with platelets, the fibrin threads form a stable blood clot.
Antithrombin (AT), a serine protease inhibitor, is the major plasma inhibitor of coagulation proteases. AT blocks the coagulation cascade by, e.g., inhibiting thrombin (factor IIa) and activated factor X (factor Xa). Heparin (unfractionated heparin) and low molecular weight heparins (LMWHs; fractionated heparin) inhibit the coagulation process through binding to AT via a pentasaccharide sequence. This binding leads to a conformational change of AT, which accelerates its inhibition of factors IIa, Xa, and other proteases involved in blood clotting. Once dissociated, heparin and LMWH are free to bind to another antithrombin molecule and subsequently inhibit more thrombin and factor Xa.
Unfractionated heparin is a mixture of glycosaminoglycans (GAGs) discovered in the liver of dogs to have anti-coagulant properties in 1916 by McLean and Howell at Johns Hopkins University. In addition to anti-coagulation, unfractionated heparin has been found to have other properties including anti-inflammation and angiogenesis. LMWHs are heparins consisting of short chains of polysaccharide, generally having molecular weight of less than 8000 Da. LMWH and heparin are both used to prevent blood from clotting inside the body, but are used in different situations in the clinic.
Heparin is available as a liquid solution administered parenterally. LMWH, such as enoxaparin, is a low molecular weight fraction of heparin. It is also available as a liquid injectable solution. The currently available brands of LMWH approved by FDA in the United States are LOVENOX® (generic name, enoxaparin) and FRAGMIN® (generic name, dalteparin).
Low molecular weight or fractionated heparin has greater specificity for blood factor Xa and factor IIa activity than unfractionated heparin. Additionally, LMWH has a more reproducible effect on activated partial thromboplastin time (aPTT), a measure of coagulation time. LWMH has a lower incidence of Heparin Induced Thrombocytopenia (HIT). Because LMWH has more predictable efficacy and a lower incidence of adverse effects such as HIT, patients can inject LMWH themselves at home, although it is also often used in the hospital. For these reasons, LMWHs have become the market-leading anticoagulant.
Protamine, a positively charged molecule, can be used to reverse anti-coagulation resulting from administration of highly negatively charged unfractionated heparin or low molecular weight heparin (LMWH). Protamine is a natural product that has been associated with supply problems, which highlights a need for additional, ideally synthetic, reversal agent options. The anti-coagulant activity of LMWH can be partially, but not fully, reversed by intravenous administration of protamine. The reason for the reduced anticoagulation reversal activity of protamine in the case of LMWH is believed to be due to a lesser binding affinity for the LMWH fraction in the blood than unfractionated heparin. Protamine must be administered slowly, due to hypotensive effects and concerns regarding anaphylaxis.
Recently, additional anticoagulant agents have begun to gain regulatory approval. Examples of such anticoagulants include dabigatran or PRADAXA®, argatroban or ARGATROBAN®, rivaroxaban or XARELTO®, apixaban or ELIQUIS®, edoxaban or LIXIANA®, and fondaparinux or ARIXTRA®. These anticoagulants inhibit either factor IIa or factor Xa from propagating coagulation.
Anticoagulants such as dabigatran, fondaparinux, rivaroxaban and apixaban have no approved reversal agent. The current state of the art for dabigatran or PRADAXA® reversal is to employ activated charcoal to attempt to remove dabigatran from the blood and to use blood transfusions. Other than Eerenberg et al. Circulation. 2011 Oct. 4; 124(14):1573-9. Epub 2011 Sep. 6., which reports that in a small clinical trial, prothrombin complex concentrate was able to reverse dabigatran, but not rivaroxaban, there is no data or clinically available antidote for reversing any of these coagulation Factor IIa or Xa inhibitors. Therefore, when patients are anti-coagulated with these agents, adverse effects associated with overdosing, particularly significant or fatal bleeds, are much more dangerous than the side effects associated with administration of unfractionated heparin. The lack of reversal agent therefore limits the use of these drugs.
For these reasons, there is a longstanding, strong, unmet clinical need for new anti-coagulation reversal agents.